Patients with elastin insufficiency present with a range of symptoms that may be associated with their arteriopathy: dyspnea, chest pain, headache, cognitive changes, hypertension and abdominal pain. In order to produce a viable treatment for this condition, its pathophysiology must be understood. Using a translational approach consisting of animal models and human studies, we have sought to 1) examine the impact of elastin arteriopathy on end organs, 2) investigate the cause of sudden death in this population, and 3) test potential therapies to treat elastin mediated vasculopathy. Impact of elastin insufficiency on end organs: The effect of elastin insufficiency on large conducting vessels has been well described, consisting of reduced elastin content and a reciprocal increase in arterial smooth muscle cell number. This change in the cell to matrix ratio produces vessels with narrow luminal diameter and thickened, poorly compliant walls. Work to date has shown that mice and humans with decreased elastin have increased resting blood pressure, higher pulse wave velocity (a marker for arterial stiffness), and reduced blood flow through the major conducting arteries. Subsequent investigation in Eln+/- mice using blood flow imaging has shown globally reduced brain perfusion relative to wild types. To investigate these findings in humans, we developed a human protocol to allow us to broadly evaluate the impact of elastin insufficiency on end organs. To date, 87 individuals have undergone complete evaluation at the NIH. Information gained so far confirms increased vascular stiffness in patients with both WS and SVAS as well as new findings related to cardiac function, end organ blood flow and arterial reactivity. Current analyses are underway looking at cardiac function, exercise tolerance, and retinal abnormalities, among others, in our cohort. Knowledge gained from this study will impact patients with WBS/SVAS, it will be important as we consider potential new therapies to balance a drugs impact on blood pressure and arterial stiffness to its impact on blood flow. It will also have an impact for understanding the changes to blood flow that occur with normal aging, a process that involves gradual loss of elastin over the lifetime. Sudden death in Williams Beuren syndrome: Individuals with elastin insufficiency are reported to have a 25-100X increased risk of sudden death; this risk is enhanced during anesthesia. A survey performed by our group in in 649 affected individuals and 1872 procedures confirmed the previously reported finding that shows increased risk of negative outcomes with anesthesia in individuals with bilateral outflow track obstruction. However, this finding does not account for all of the anesthesia risk. Notable patients in our cohort without significant outflow tract obstruction experienced need for cardiac resuscitation during surgery, suggesting the need to further investigate the cause of anesthesia risk in this group. We questioned whether features of the heart itself may contribute to sudden death risk in this population. Evaluation of coronaries in both the WBS patients and Eln+/- mouse found increased tortuosity for the vessels, including hairpin turns and acute branching angles. In addition, patients were found to have frequent t wave irregularities (t wave flattening and inversion) and mice showed increase susceptibility to arrythmia and collapse with anesthesia and stress. Further investigation of dissociated cardiomyoctes showed abnormalities of calcium handling associated with action potential elongation and frequent early after depolarizations. Taken together, we believe that susceptibility to cardiovascular decompensation with anesthesia in patients with elastin insufficiency is likely multifactorial. The known systemic vascular features of condition including stenosis, stiffness, and hypertension predispose to challenges with perfusion of the heart if blood pressure is acutely lowered with anesthesia induction or throughout the procedure. Negative effects are then amplified by abnormalities of the coronaries including narrowing and tortuosity that may lead to local regions of cardiac hyoperfusion and possible hypoxia. In the setting of preexisting abnormalities of calcium handling and rhythm disturbance, we believe that this puts our patients at increased risk of sudden death. Additional work investigating the role of KATP channels in contributing to this outcome is underway. Therapies for elastin mediated disease: As stated above, individuals with elastin insufficiency have stiff blood vessels with narrow caliber. Previous work by our lab showed that this combination of findings contributed to decreased cerebral perfusion in Eln+/- mice. Treatment with minoxidil, at KATP channel opener, however, shows promise for treatment of elastin mediated vascular disease. When mutant mice were treated from weaning to 3 months of age with minoxidil, blood pressure normalized, apparent stiffness was reduced and perfusion to the brain improved. RNAseq analysis shows that the drug works initially by inducing vasodilation that, when persistent, leads to matrix remodeling. Once completed, the vascular remodeling remains stable for some time after the drug is removed. This year we focused on the pulmonary vascular tree, an area of particular concern for patients with elastin insufficiency because the disease their tends to affect multiple vessels, leading to challenges for surgical or even balloon intervention. In our mouse model, vessels are also narrow and pressure is higher. When evaluated by latex injection, we also find that the vascular tree is longer, a finding that continues to increase over time. When treated with minoxidil, the caliber of the vessels improves as does the arterial resistance. We are currently working to assess the feasibility of a trial of minoxidil for the treatment of pulmonary vascular disease not amenable to surgical intervention. The decision to proceed, to some degree, will be predicated on a more complete understanding the role of KATP channels in the heart and their possible role in anesthesia associated sudden death. It is important to not that a recent minoxidil trial took place looking at carotid intimal medial thickness as an outcome in a wide range of patients. The trial failed for that specific outcome but it was tolerated over all in the tested population and a signal for increased lumen diameter was noted although it was not a primary study outcome.